Type 2 diabetes Mellitus is a devastating disease of epidemic proportions, which is threatening individual lives as well as sovereign economies worldwide. Defective function and death of insulin-producing pancreatic ?-cells is a hallmark of diabetes mellitus. In this proposal we aim to elucidate molecular mechanism(s) underlying ?-cell dysfunction and demise, which are mediated by a thus far unrecognized hormone released by the liver: kisspeptin1. In preliminary findings, we observe in mouse models which mimic human diabetes mellitus, the liver produces and releases into the circulation excessive amounts of kisspeptin1. Kisspeptin1 reaches the pancreatic ?-cells and acts through its receptor Kiss1R, which is located on ?-cells to inhibit cyclic AMP production. Reduction in ?-cell cyclic AMP levels has several potential consequences which are observed in humans with type 2 diabetes mellitus: 1) it reduces glucose-stimulated insulin secretion from ?-cells; 2) it reduces the response to incretin hormones in potentiating glucose simulated insulin secretion; 3) by reducing cyclic AMP levels, it renders ?-cells susceptible to programmed cell death (apoptosis) as a consequence of increased cellular stress (endoplasmic reticulum stress, unfolded protein response and oxidative stress). The proposed studies aim to further elucidate the mechanistic underpinnings of our preliminary findings and to test whether the findings apply to humans with type 2 diabetes mellitus. The proposed studies are significant because they may lead to identification of molecular targets and therapeutic approaches for treating humans with diabetes mellitus and preventing or reversing ?-cell dysfunction and -death.